In the CE/MPA substudy of WHI an increased risk of coronary heart disease
(CHD) events (defined as non-fatal myocardial infarction and CHD death) was
observed in women receiving CE/MPA compared to women receiving placebo (37
vs 30 per 10,000 women years). The increase in risk was observed in year one
and persisted. (See CLINICAL PHARMACOLOGY, Clinical
Studies.)

In the same substudy of WHI, an increased risk of stroke was observed in women
receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000
women-years). The increase in risk was observed after the first year and persisted.

In postmenopausal women with documented heart disease (n = 2,763, average
age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular
disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with
CE/MPA (0.625mg/2.5mg per day) demonstrated no cardiovascular benefit. During
an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the
overall rate of CHD events in postmenopausal women with established coronary
heart disease. There were more CHD events in the CE/MPA-treated group than
in the placebo group in year 1, but not during the subsequent years. Two thousand
three hundred and twenty one women from the original HERS trial agreed to
participate in an open label extension of HERS, HERS II. Average follow-up
in HERS II was an additional 2.7 years, for a total of 6.8 years overall.
Rates of CHD events were comparable among women in the CE/MPA group and the
placebo group in HERS, HERS II, and overall.

Venous thromboembolism (VTE)In the Women's Health Initiative (WHI) study, an increased risk of
deep vein thrombosis was observed in women receiving CE compared to placebo.
In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep
venous thrombosis and pulmonary embolism, was observed in women receiving
CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000
women-years in the CE/MPA group compared to 16 per 10,000 women-years in the
placebo group. The increase in VTE risk was observed during the first year
and persisted. (See CLINICAL PHARMACOLOGY, Clinical
Studies.)
If feasible, estrogens should be discontinued at least 4 to 6 weeks before
surgery of the type associated with an increased risk of thromboembolism,
or during periods of prolonged immobilization.

Malignant neoplasms

Endometrial cancerThe use of unopposed estrogens in women with intact uteri has been
associated with an increased risk of endometrial cancer. The reported endometrial
cancer risk among unopposed estrogen users is about 2- to 12-fold greater
than in non-users, and appears dependent on duration of treatment and on estrogen
dose. Most studies show no significant increased risk associated with use
of estrogens for less than one year. The greatest risk appears associated
with prolonged use, with increased risks of 15- to 24-fold for five to ten
years or more and this risk has been shown to persist for at least 8 to 15
years after estrogen therapy is discontinued.

Clinical surveillance of all women taking estrogen/progestin combinations
is important. Adequate diagnostic measures, including endometrial sampling
when indicated, should be undertaken to rule out malignancy in all cases of
undiagnosed persistent or recurring abnormal vaginal bleeding. There is no
evidence that the use of natural estrogens results in a different endometrial
risk profile than synthetic estrogens of equivalent estrogen dose. Adding
a progestin to estrogen therapy has been shown to reduce the risk of endometrial
hyperplasia, which may be a precursor to endometrial cancer.

Breast cancerThe use of estrogens and progestins by postmenopausal women has been
reported to increase the risk of breast cancer. The most important randomized
clinical trial providing information about this issue is the Women's Health
Initiative (WHI) substudy of CE/MPA (see CLINICAL PHARMACOLOGY, Clinical
Studies). The results from observational studies are generally consistent
with those of the WHI clinical trial and report no significant variation in
the risk of breast cancer among different estrogens or progestins, doses,
or routes of administration.
The CE/MPA substudy of WHI reported an increased risk of breast cancer in
women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies
have also reported an increased risk for estrogen/progestin combination therapy,
and a smaller increased risk for estrogen alone therapy, after several years
of use. In the WHI trial and from observational studies, the excess risk increased
with duration of use. From observational studies, the risk appeared to return
to baseline in about five years after stopping treatment. In addition, observational
studies suggest that the risk of breast cancer was greater, and became apparent
earlier, with estrogen/progestin combination therapy as compared to estrogen
alone therapy.
In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone
and/or estrogen/progestin combination hormone therapy. After a mean follow-up
of 5.6 years during the clinical trial, the overall relative risk of invasive
breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall
absolute risk was 41 vs. 33 cases per 10,000 women-years, for CE/MPA compared
with placebo. Among women who reported prior use of hormone therapy, the relative
risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs.
25 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women
who reported no prior use of hormone therapy, the relative risk of invasive
breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000
women-years for CE/MPA compared with placebo. In the same substudy, invasive
breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA
group compared with the placebo group. Metastatic disease was rare with no
apparent difference between the two groups. Other prognostic factors such
as histologic subtype, grade and hormone receptor status did not differ between
the groups.
The use of estrogen plus progestin has been reported to result in an increase
in abnormal mammograms requiring further evaluation. All women should receive
yearly breast examinations by a healthcare provider and perform monthly breast
self-examinations. In addition, mammography examinations should be scheduled
based on patient age, risk factors, and prior mammogram results.

Dementia

In the Women's Health Initiative Memory Study (WHIMS), 4,532 generally healthy
postmenopausal women 65 years of age and older were studied, of whom 35% were
70 to 74 years of age and 18% were 75 or older. After an average follow-up of
4 years, 40 women being treated with CE/MPA (1.8%, n=2,229) and 21 women in
the placebo group (0.9%, n=2,303) received diagnoses of probable dementia. The
relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21
– 3.48), and was similar for women with and without histories of menopausal
hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA
versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute
excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether
these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY,
Clinical Studies and PRECAUTIONS,
Geriatric Use.)

Gallbladder disease

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery
in postmenopausal women receiving estrogens has been reported.

Hypercalcemia

Estrogen administration may lead to severe hypercalcemia in patients with breast
cancer and bone metastases. If hypercalcemia occurs, use of the drug should
be stopped and appropriate measures taken to reduce the serum calcium level.

Visual abnormalities

Retinal vascular thrombosis has been reported in patients receiving estrogens.

Discontinue medication pending examination if there is sudden partial or complete
loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination
reveals papilledema or retinal vascular lesions, estrogens should be permanently
discontinued.

PRECAUTIONS

General

Addition of a progestin when a woman has not had a hysterectomy.Studies of the addition of a progestin for 10 or more days of a cycle
of estrogen administration, or daily with estrogen in a continuous regimen,
have reported a lowered incidence of endometrial hyperplasia than would be
induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor
to endometrial cancer. There are, however, possible risks that may be associated
with the use of progestins with estrogens compared to estrogen-alone treatment.
These include a possible increased risk of breast cancer.

Elevated blood pressureIn a small number of case reports, substantial increases in blood
pressure have been attributed to idiosyncratic reactions to estrogens. In
a large, randomized, placebo-controlled clinical trial, a generalized effect
of estrogens on blood pressure was not seen. Blood pressure should be monitored
at regular intervals with estrogen use.

HypertriglyceridemiaIn patients with pre-existing hypertriglyceridemia, estrogen therapy
may be associated with elevations of plasma triglycerides leading to pancreatitis
and other complications.

Impaired liver function and past history of cholestatic jaundiceEstrogens may be poorly metabolized in patients with impaired liver
function. For patients with a history of cholestatic jaundice associated with
past estrogen use or with pregnancy, caution should be exercised and in the
case of recurrence, medication should be discontinued.

HypothyroidismEstrogen administration leads to increased thyroid-binding globulin
(TBG) levels. Patients with normal thyroid function can compensate for the
increased TBG by making more thyroid hormone, thus maintaining free T4
and T3 serum concentrations in the normal range. Patients dependent
on thyroid hormone replacement therapy who are also receiving estrogens may
require increased doses of their thyroid replacement therapy. These patients
should have their thyroid function monitored in order to maintain their free
thyroid hormone levels in an acceptable range.

Fluid retentionBecause estrogens may cause some degree of fluid retention, patients
with conditions that might be influenced by this factor, such as a cardiac
or renal dysfunction, warrant careful observation when estrogens are prescribed.

HypocalcemiaEstrogens should be used with caution in individuals with severe hypocalcemia.

Ovarian cancerThe CE/MPA sub-study of WHI reported that estrogen plus progestin
increased the risk of ovarian cancer. After an average follow-up of 5.6 years,
the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95%
confidence interval 0.77-3.24) but was not statistically significant. The
absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000
women-years. In some epidemiological studies, the use of estrogen alone, in
particular for ten or more years, has been associated with an increased risk
of ovarian cancer. Other epidemiologic studies have not found these associations.

Exacerbation of endometriosisEndometriosis may be exacerbated with administration of estrogens.
A few cases of malignant transformation of residual endometrial implants have
been reported in women treated post-hysterectomy with estrogen alone therapy.
For patients known to have residual endometriosis post-hysterectomy, the addition
of progestin should be considered.

Exacerbation of other conditionsEstrogens may cause an exacerbation of asthma, diabetes mellitus,
epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic
hemangiomas and should be used with caution in women with these conditions.

Patient information

Physicians are advised to discuss the PATIENT INFORMATION
leaflet with patients for whom they prescribe Climara (estradiol transdermal) .

Laboratory Tests

Estrogen administration should be initiated at the lowest dose approved for
the indication and then guided by clinical response rather than by serum hormone
levels (e.g. estradiol, FSH).

Carcinogeneses, Mutagenesis, And Impairment Of Fertility

Long-term continuous administration of estrogen, with and without progestin,
in women with and without a uterus, has shown an increased risk of endometrial
cancer, breast cancer, and ovarian cancer. (See BOXED
WARNINGS, WARNINGS and PRECAUTIONS.)

Long-term continuous administration of natural and synthetic estrogens in certain
animal species increases the frequency of carcinomas of the breast, uterus,
cervix, vagina, testis, and liver.

Pregnancy

Climara (estradiol transdermal) should not be used during pregnancy. (See CONTRAINDICATIONS.)

Nursing Mothers

Estrogen administration to nursing mothers has been shown to decrease the quantity
and quality of the milk. Detectable amounts of estrogens have been identified
in the milk of mothers receiving this drug. Caution should be exercised when
Climara (estradiol transdermal) is administered to a nursing woman.

Pediatric Use

Estrogen replacement therapy has been used for the induction of puberty in
adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric
patients have not otherwise been established. Large and repeated doses of estrogen
over an extended time period have been shown to accelerate epiphyseal closure,
which could result in short adult stature if treatment is initiated before the
completion of physiologic puberty in normally developing children. If estrogen
is administered to patients whose bone growth is not complete, periodic monitoring
of bone maturation and effects on epiphyseal centers is recommended during estrogen
administration. Estrogen treatment of prepubertal girls also induces premature
breast development and vaginal cornification, and may induce vaginal bleeding.
In boys, estrogen treatment may modify the normal pubertal process and induce
gynecomastia. (See INDICATIONS and DOSAGE
AND ADMINISTRATION.)

Geriatric Use

There have not been sufficient numbers of geriatric patients involved in clinical
studies utilizing Climara (estradiol transdermal) to determine whether those over 65 years of age differ
from younger subjects in their response to Climara (estradiol transdermal) .

In the Women's Health Initiative Memory Study, including 4,532 women 65 years
of age and older, followed for an average of 4 years, 82% (n=3,729) were 65
to 74 while 18% (n=803) were 75 and over. Most women (80%) had no prior hormone
therapy use. Women treated with conjugated estrogens plus medroxyprogesterone
acetate were reported to have a two-fold increase in the risk of developing
probable dementia. Alzheimer's disease was the most common classification of
probable dementia in both the conjugated estrogens plus medroxyprogesterone
acetate group and the placebo group. Ninety percent of the cases of probable
dementia occurred in the 54% of women that were older than 70. (See BOXED
WARNING and WARNINGS, Dementia.)

Last reviewed on RxList: 10/2/2008
This monograph has been modified to include the generic and brand name in many instances.